Important medically-related issues exist as to why acute pain is perceived with high intensity despite the presence of extensive endogenous pain-modulating systems, and why chronic intractable pain arises from pathophysiological sequelae of nerve injury without consistency of symptomatology, etiological factors; and treatment strategies across patient populations. This necessitates an in depth understanding of how spinal excitatory systems, of which the tachykinin substance P (SP) represents a prototypic regulatory peptide, functionally interact with endogenous opioid systems to maintain functional homeostasis of nociceptive signaling and compensatory antinociceptive responsiveness at spinal and supra spinal levels. The foundation of present proposal is based on recent data obtained from in vivo pharmacological testing, and complementary biochemical analyses, of a chimeric peptide newly synthesized by our group: a heptapeptide consisting of overlapping NH2- and COOH-terminal functional domains of the opioid endomorphin-2(EM-2) and SP, respectively. The chimeric molecule YPFFGLM-NH2, designated ESP7, displays agonist activity at both the u-opioid (MOR) and SP (SPR) receptors. Administration of low concentrations of ESP7 by the intrathecal route produces long-lasting analgesia in the rat tail-flick text that is blocked by prior treatment with the opioid antagonist naltrexone. Repeated administration of ESP7 produces opioid-dependent analgesia without loss of potency over five days. In contrast, repeated administration of ESP7 in the presence of the selective SPR antagonist RP67580 results in a rapid loss of analgesic potency consistent with the development of opioid tolerance observed following administration of MOR-preferring opioids; post-hoc administration of ESP7 also effects partial rescue of opioid responsiveness in tolerant animals. We conclude that in vivo activation of SPR-expressing spinal neurons is functionally linked to inhibition of or delayed onset of opioid tolerance, and further hypothesize that coincident activation of MOR- and SPR-expressing systems mimics an ongoing state of reciprocal excitation and inhibition normally encountered in nociceptive processing. Our overall testable hypothesis is thus: chimeric peptides, composed oftwo independent but overlapping moieties contributed by an opioid peptide and substance P, are novel non-tolerance forming analgesics via their combined agonist action at functionally interactive classes of spinal and supra spinal receptors.Within this framework we propose the following three Specific Aims. 1. To evaluate chimeric peptides as novel analgesic agents through targeting of interactive spinal and supra spinal opioid and tachykinin neural systems, 2. To evaluate chimeric peptides in preclinical models of opioid tolerance and of acute and chronic pain, 3. To develop chimeric peptides with overlapping but distinct functional moieties derived from NH2-terminal domains of delta and kappa opioids and the COOH-terminal domain of SP as novel analgesics.